We have generated mutant mice that harbor null alleles of DJ-1 and PINK1. Both genes are linked to recessive form of early-onset familial Parkinson's disease (PD). Our published and unpublished data indicate that DJ-1 deficient mice develop progressive age-dependent hypolocomotion, dopamine system dysregulation, body weight loss and skeletal muscle degeneration. Similarly, muscle degeneration has recently been reported in PINK1 deficient flies. In contrast, PINK1 null mice only display very mild phenotypes (our unpublished data). Recently, PD cases that are heterozygous for DJ-1 and PINK1 mutations have been reported. We reason that DJ-1 and PINK1 might be components of a biochemical pathway and that DJ-1;PINK1 double mutant mice might develop important phenotypes that are not captured by either DJ-1 deficiency or PINK1 deficiency alone. We have successfully obtained DJ-1;PINK1 double null allele (DJ-1 and PINK1 are 11.9 Mb apart). To our surprise, deficiency for both DJ-1 and PINK1 leads to early embryonic lethality, further reinforcing the idea that DJ- 1 and PINK1 might be components of a biochemical pathway that is crucial for cell survival in multiple tissues. We propose to generate a series of mutant mouse lines with intermediate DJ-1 PINK1 gene doses in order to obtain intermediate phenotypes between early embryonic lethality (DJ-1;PINK1 double mutants) and muscle degeneration but no dopamine neuron loss (DJ-1 single mutants). These mice will be important tools to investigate DJ-1 and PINK1 function and their interactions related to the pathogenesis in Parkinson)s disease as well as in other degenerative diseases. PUBLIC HEALTH RELEVANCE: Recently published studies and our own data suggest that two genes, DJ-1 and PINK1, may work together and play important roles in Parkinson's disease and other degenerative diseases. We propose to generate animal models to examine in detail such a biochemical pathway that is important for different degenerative disease. Our results will point to new therapeutic targets and therapeutic approaches.